Even though SSRIs are often demonized by social media and the lay public, I personally know a great number of people who were helped by them. In this article, I try to paint a fair picture of this misunderstood class of drugs.
Personal experience with SSRIs
A couple of years ago, after my third year of med school, I took a year off to travel the world. I was in India at the time and I learned about Vipassana and Buddhism. I thought a lot about whether the traits that Buddhists acquire through years of mind-training can be pharmacologically replicated.
After a 10 day Vipassana retreat in Kathmandu, I decided to take a very small dose of escitalopram (2.5mg – usual dose is 10mg) for self-improvement purposes – I wanted to pharmacologically replicate stoicism and some other Buddhist traits.
I started with only 1.25mg. At the time I was with several other travellers in Pokhara. For the first couple of days, my feelings of stress and worry about returning home (my trip was about to come to an end) were exchanged for feeling hot (temperature-wise), sleepiness, and apathy.
After about 2-3 weeks, I remember it to this day, I was reading Tools of Titans by Tim Ferris, and it suddenly occurred to me that my feelings of stress and worry were completely gone and instead, there was a form of calm happiness.
I ended up taking the escitalopram for roughly a year. During this time, I was quite content and that year was perhaps among the top 5 most happy years of my life. During this year, I also made progress in a number of life domains. For example, I studied a lot of science, I filled over a dozen journals, I found a girlfriend I was incredibly happy with at the time, I made a decent amount of money on the side, and I built a lot of useful habits that serve me to this day.
Sometimes I went for morning walks and I remember how I felt a welling of euphoria about how content I was. I am sure that escitalopram overall helped me – how much though is hard to say as there were many other things going on in parallel.
During this time, I also became very rational, perhaps even robot-like, in my decision-making. Unfortunately, the price of “stoicism” was emotional intensity, and my ability to feel deep emotions, whether positive or negative – was reduced (though not lost).
I eventually tapered off because of four reasons:
- Escitalopram reduced some of my ability to experience negative emotions. I believe that, in healthy amounts, negative emotions are important for learning, personal growth, and change.
- Escitalopram killed my brain’s ability to generate anxiety. For many, this is desired, but for me, it is not. I believe that the difference between the feeling of contentment and the feeling of meaning is partially a function of anxiety levels. I would rather have meaning than contentment.
- I had less empathy for others, perhaps as true empathy is not really possible with a brain that is incapable of generating anxiety.
- I felt that after the initial honeymoon phase was over, escitalopram crushed my emotions for my then-girlfriend and I felt that I was “less in love” with her than I would have otherwise been.
Overall, escitalopram was a very interesting, pleasant, and productive experience though I would not want to do it again. In my opinion, a microdose of escitalopram blows Ashwagandha out of the water and if people are going down that route already, namely using exogenous molecules to improve mood, then they may as well opt for the better ones.
I discuss my experience with vortioxetine, an atypical SSRI, here.
People I know who were helped by SSRIs
There is a difference between looking at the current public opinion about things (i.e., “SSRIs are bad”; carbs make you fat) and personal experience. I know about a dozen people who were helped by SSRIs and, aside from a reduction in sex drive, I do not know a single person who was harmed by them – at least not in an obvious way.
- My mum used 2.5mg of escitalopram during her chemotherapy for breast cancer and for her, it was a gamechanger. After her treatment was over, she tapered off.
- A friend of mine finds low doses of either escitalopram or vortioxetine useful for seasonal affective disorder.
- Another friend of mine found a lot of help in 10mg of escitalopram while suffering from longCOVID and, according to him, it was one of the most important weapons that helped him to recover.
- One of my best friends uses subclinical doses of SSRIs to reduce his background anxiety and he likes the rationality SSRIs give.
- The girlfriend of a good friend of mine was struggling with depression and feelings of worthlessness. Ever since starting 5mg of escitalopram, her life has been on a huge upward trajectory and she is going to Harvard for an internship this summer. She is still on it though plans on tapering off in a couple of months after thing have “stabilized” a bit more.
- One friend used SSRIs specifically to reduce his libido. His libido was not reduced though he “could go forever”. He came off quickly.
- When I struggled with symptoms of depression, vortioxetine was a boon.
- The ex-girlfriend of a good friend used sertraline during a depressive episode. She felt much better quickly though her sex drive tanked while she was on it. Overall, SSRIs helped their relationship because she was less of an emotional wreck.
- One friend uses low doses of escitalopram from time to time to help with stress (he is a PhD and the research environment he is in is quite shitty). The last time I spoke to him he said he stopped for good because escitalopram replaces his aggression with complacency, which is not conducive to getting things done.
- A woman I dated used fluoxetine after her brother died in a motorcycle accident. She had been depressed for 2 years but not until hopping on the SSRI could she really make progress in terms of processing her trauma. Also, after starting the drug her sex drive soared (or more likely: unleashed her sex drive that had been depressed by depression).
SSRIs – Introduction
Anxiety disorders are quite common – possibly more common than most people can imagine. Similar things hold for depression or sub-depressive states. A lot of people make it somehow through the day (…after day…) while suffering terribly without anyone knowing.
For both conditions, serotonin-reuptake inhibitors (SSRIs) are often prescribed as a first-line treatment.
SSRIs block the serotonin transporter (SERT), the transport protein responsible for the reuptake of serotonin. If this protein is blocked, serotonin accumulates in the synaptic cleft in all of the neural networks innervated by serotonergic neurons, which has a host of downstream consequences.
Serotonin plays a vital role in fear, mood, memory, appetite, sleep, pain perception, and sexual desire.
The serotonin functions recognized by the wider public such as increased self-confidence, cognitive flexibility, reduction in aggression, and calmness, are in part a result of the inhibition of pathways associated with fear. The removal of this “background fear” increases self-confidence and calmness.
Low levels of serotonin are also associated with poor agreeableness, irrational coping mechanisms, impulsivity, overanalyzing, and poor ability to just “be present”. SSRIs are known to change all of these traits to some extent.
Serotonin also plays a crucial role in shaping one’s self-perception and confidence. One theory suggests that individuals with lower serotonin levels may view themselves as being at the bottom of the social hierarchy, a concept known as the “neurobiochemistry of defeat.”
Moreover, serotonin is also implicated in regulating cognitive flexibility, which is thought to be in part by its modulation of basal ganglia systems. When people who are “locked” into rigid mental and behavioral patterns are given SSRIs or other serotonergic drugs, the thought loops, rumination, and cognitive rigidity often lessen. Therefore, serotonergic drugs are often prescribed for OCD, depression, and eating disorders.
Serotonin is more thoroughly discussed here: A Brief Introduction to Neurotransmitters.
When serotonin levels increase, among other things, the activity of fear pathways abates (resulting in a state of calmness), neurogenesis is ramped up within the hippocampus, and a host of cellular changes between and within neurons are set in motion, including receptor reregulation and widespread changes in gene expression.
Broadly speaking, SSRIs are thought to influence individuals to gravitate more towards the center of the “big five” personality traits, regardless of their initial standing at either extreme.
Two commonly reported concerns of long-term SSRI use are sexual dysfunction and emotional blunting. There are reports of these continuing for months or years after stopping the medication. I discuss this in more detail below.
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Upsides of SSRIs
SSRIs have demonstrated a certain degree of effectiveness in alleviating symptoms of both anxiety and depression.
Serotonin has an inhibitory effect on neural pathways associated with the fear response. In part because of this, SSRIs reduce anxiety, “neediness”, and perceived stress, all while promoting resilience, self-confidence, and greater self-sufficiency.
Furthermore, by modulating basal ganglia function, SSRIs reduce the tendency for rumination and are often able to banish intrusive thoughts. The elevation in serotonin also helps with the birth and survival of hippocampal neurons.
Because of these upsides, SSRIs have their rightful place for treating mental health issues.
Downsides of SSRIs
Even though SSRIs are (somewhat) mood-brightening, resilience-enhancing, and have anti-anxiety effects, SSRIs diminish the intensity of felt emotions and are therefore “numbing” agents that flatten both the peaks as well as the troughs. For example, SSRIs are well known to dampen the intensity of interpersonal empathy and romantic love.
This flattening effect has upsides and downsides. As an upside, people tend to make more rational decisions instead of emotional ones. As a downside, diminishing the intensity of one’s felt experience is not a particularly “life-enriching” thing to do.
Given that most people probably take SSRIs for far longer than necessary, millions of people around the world take these drugs, in my opinion, needlessly – only to discover after coming off that they had been living somewhat lifelessly on autopilot.
Furthermore, in kinds of depression in which anxiety or intense rumination plays only a minor role but which are mainly characterized by meaninglessness or apathy, SSRIs may actually make things worse. Whenever serotonin signaling surpasses a certain threshold, dopamine signaling falls due to serotonergic modulation of midbrain dopaminergic systems. Thus, SSRIs increase serotonin somewhat at the expense of dopamine. This state has been aptly termed “SSRI-induced amotivational syndrome”.
It is in part because of this that SSRIs routinely reduce libido and cause emotional blunting (even if users are not aware of it). Even though emotional blunting is useful in many cases, apathy is rarely a desirable state to be in. Furthermore, SSRIs do nothing in terms of sleepiness and fatigue. They often amplify these features further – especially at higher doses.
Furthermore, if somebody takes an SSRI, the SERT transporter is blocked throughout the brain and body (and not just where we want it to be blocked). For example, this includes the SERT transporters in brain sites responsible for appetite + sleep + libido, the gastrointestinal system, the heart, and all of the other places where SERT transporters are expressed.
Under physiological conditions, serotonin signaling in one region is independent of serotonin signaling in any other region (serotonin signaling is discussed in more detail here). But when an SSRI is administered, all of these formerly independent regions are activated in one go. This is part of the reason why SSRIs have a number of side effects.
However, in my opinion, many of these downsides can be avoided by taking subclinical doses instead of clinical ones (e.g., 1.25mg or 2.5mg of escitalopram instead of 10mg+).
Risks & side effects of SSRIs
The major upside of SSRIs is that they are safe in overdose meaning that they cannot be used for committing suicide, which cannot be said for the dirty tricyclics or the mighty MAO-inhibitors – the former are deadly in overdose, and the latter if intentionally or unintentionally combined with serotonergic drugs. This may be part of the reason why many doctors like to prescribe SSRIs (“I am covered.”).
However, even though safe in overdose, SSRIs are by no means the harmless drugs the drug companies make them out to be (though probably less harmful than what the public makes them out to be). They have a lot of side effects, including weight gain, fatigue, sexual dysfunction, and emotional blunting – particularly at higher doses. To counteract these side effects, the NDRI bupropion is often prescribed as an add-on, a strategy which hits all three major monoamines (serotonin, noradrenaline, and a bit of dopamine). Bupropion is discussed in more detail here.
Furthermore, SSRIs also have a horrible discontinuation syndrome (which is great for maintaining drug sales) – at least for some people. In fact, given the symptomatic overlap of discontinuation syndrome with actual depression, there is no way of telling whether SSRIs do indeed decrease recidivism or merely prevent their own withdrawal syndrome.
It seems that a lot of the published literature on SSRIs is tainted by the invasion of academic psychiatry by the industry in the 1990s and beyond, a time when most SSRIs were brought to market. This is not to say that there are no honest, accurate, unbiased, and useful papers that stand up to the ultimate scientific test of replication. There certainly are but they are certainly not the norm.
Regardless, it took over 20 years before some of the more severe side effects of SSRIs such as valvular heart disease, increased risk of death from bleeding and hemorrhage, and PSSD became more widely known.
One of the truly dangerous side effects of SSRIs, other than treating depression suboptimally, is Post-SSRI-Sexual-Dysfunction (PSSD), which for some unfortunate users can be permanent. PSSD is characterized by emotional blunting, cognitive dysfunction, and famously, genital insensitivity. Even though likely underreported, PSSD seems to be quite rare. (some credible estimates range from 0.2-1% – online-survey are likely highly biased).
Judged by the content of this Reddit group, PSSD has destroyed a lot of lives and healing is rare – r/PSSD.
The mechanism of PSSD is unknown. Theories include neurotoxicity, serotonin-mediated nerve fiber degeneration, a lasting imbalance in gene expression changes, or “memory” formation in certain neural networks – analogous to tardive dyskinesias after antipsychotics or HPPD after psychedelics. In sum, nobody has any idea how it is caused and why some people get it and others do not.
The neglection of dopamine
There seems to be a specific pattern of depressive symptoms that is inadequately addressed by serotonergic antidepressants. Among these symptoms are anhedonia, reduced motivation, loss of interest, fatigue, and apathy.
Furthermore, treating patients with so-called “atypical” features with SSRIs often exacerbates the issue causing a state of so-called “amotivational syndrome”, perhaps in part caused by (excess) serotonin further suppressing dopamine signaling.
I discuss my thoughts on the importance of dopamine, and what to do about it, here: The Brutal Neglect of Dopamine
Different kinds of SSRIs
The SSRIs all differ in their chemical structure, binding profiles, and pharmacokinetics. Their functional effects are broadly similar.
Classical SSRIs
- Fluoxetine (Prozac) is the “dirtiest”, meaning that it binds to a variety of different receptors. Among other things, it blocks 5-HT2C receptors, which increases dopamine and noradrenaline levels in most parts of the brain. Therefore, it is also considered the most activating of the classical SSRIs. It is also the least likely to cause withdrawal due to its absurdly long half-life.
- Fluvoxamine is a relatively clean SSRI but with an appreciable affinity for the poorly understood sigma1-receptor.
- Citalopram is slightly sedating because of its affinity for histamine receptors.
- Escitalopram, the s-enantiomer of citalopram, is the “prototypical” SSRI. It is the cleanest because it is the most SERT-selective. Next to binding to the typical SSRI site, it also binds to an allosteric site which decreases SERT performance, and therefore it may increase serotonin levels more than other SSRIs. It has a comparatively low incidence of sexual dysfunction.
- Paroxetine is the most potent in terms of SERT occupation. It also has a slight affinity for NET. Because it is the most anticholinergic of the SSRIs, it is rarely used as a first-line treatment anymore.
- Sertraline has an appreciable affinity for the dopamine transporter and is, therefore, an often-used “all-rounder”. Unfortunately, it has a high incidence of sexual dysfunction.
SSRIs + serotonin receptor modulators
- Vortioxetine is the newest, quite effective, and might improve cognition independent of its antidepressant effects. Furthermore, it has a lower tendency to cause sexual dysfunction, insomnia, weight gain, and emotional blunting compared to classical SSRIs. Next to being an SSRI, it activates 5HT1A/B receptors and blocks 5HT7 and 5HT3 receptors. The biggest downside is that it causes nausea for some people, particularly in the initial stages.
- Vilazodone is similar to vortioxetine. It is a 5HT1A agonist and causes fewer sexual side effects and emotional blunting than classical SSRIs.
- Nefazodone is reported to have greater effects on anxiety levels than vortioxetine and vilazodone. Unfortunately, it comes with a rare risk of causing fulminant liver failure and is therefore rarely prescribed. It blocks 5HT2C and 5HT2A receptors. Some patients claim that “it is the only drug that ever worked”, thus it was brought back to market in many countries where it was taken off.
SNRIs
SNRIs are often touted to be superior to SSRIs because they have “dual-action”, but according to the psychiatrists I have talked to (and according to the available data) they are not really more effective than the classical SSRIs – even if their marketing may lead people to believe otherwise.
- Venlafaxine (Effexor) has been wrongly classified as an SNRI – at low doses, it is almost a pure SSRI as it has a SERT:NET-ratio of about 15:1. It is among the most energizing (“Prozac with a punch”), though comes with increased side effects. Venlafaxine’s superior efficacy may be due to it being an amphetamine derivative and as such, it binds to and affects SERT differently compared to other SSRIs. Reportedly, it is the one with the most troubling withdrawal and coming off is often described as “awful”. It is sometimes combined with mirtazapine (“California Rocket Fuel”).
- Duloxetine (Cymbalta), a true SNRI with a SERT:NET-ratio of about 3:1, boosts both serotonin and noradrenaline signaling. Furthermore, there is a potent inhibition of prefrontal dopamine reuptake, given that most of the prefrontal dopamine reuptake is carried out by the noradrenaline transporter (NET).
- Milnacipran is the most noradrenergic of the SSRIs (SERT:NET-ratio of 1:3). Unfortunately, its half-life is quite short (8h) and therefore it needs to be taken twice daily.
“Tried one, tried them all”
There is this saying going around in psychiatry circles “Tried one, tried them all”. This is only partially correct. While their main mechanism is similar (elevating serotonin), there are two key differences between the various kinds of SSRIs.
- Different kinds of SSRIs bind to different non-SERT targets and therefore have different effects. For example, citalopram is sedating, vs. fluoxetine is activating.
- Different SSRIs bind differently to their targets and therefore affect the targets in different ways (binding site; on/off rate of the inhibitor at the target). For example, venlafaxine binds differently to SERT than duloxetine or sertraline. Therefore, even if different SSRIs had the exact same binding profile, they would “feel” a little different.
- The life situation of a person often changes. Quite often the first go with a specific drug is “amazing” and during the second go “I felt nothing” – or vice versa.
Sources & further information
- Website: Reddit – r/Post-SSRI Sexual Dysfunction
- Scientific article: Emotional Blunting, Cognitive Impairment, Bone Fractures, and Bleeding as Possible Side Effects of Long-Term Use of SSRIs
- Scientific article: Post-SSRI Sexual Dysfunction (PSSD): Biological Plausibility, Symptoms, Diagnosis, and Presumed Risk Factors
Disclaimer
The content available on this website is based on the author’s individual research, opinions, and personal experiences. It is intended solely for informational and entertainment purposes and does not constitute medical advice. The author does not endorse the use of supplements, pharmaceutical drugs, or hormones without the direct oversight of a qualified physician. People should never disregard professional medical advice or delay in seeking it because of something they have read on the internet.